Targeting H3K4 trimethylation in Huntington disease.

TitleTargeting H3K4 trimethylation in Huntington disease.
Publication TypeJournal Article
Year of Publication2013
AuthorsVashishtha, M, Ng, CW, Yildirim, F, Gipson, TA, Kratter, IH, Bodai, L, Song, W, Lau, A, Labadorf, A, Vogel-Ciernia, A, Troncosco, J, Ross, CA, Bates, GP, Krainc, D, Sadri-Vakili, G, Finkbeiner, S, Marsh, JL, Housman, DE, Fraenkel, E, Thompson, LM
JournalProc Natl Acad Sci U S A
Date Published2013 Aug 6
KeywordsAnimals, Animals, Genetically Modified, Blotting, Western, Brain, Brain-Derived Neurotrophic Factor, Cells, Cultured, Drosophila melanogaster, Female, Gene Expression Profiling, Histones, Humans, Huntington Disease, Lysine, Male, Methylation, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Nerve Tissue Proteins, Neurons, Oxidoreductases, N-Demethylating, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23872847
PubMed Central IDPMC3740882
Grant List1F31 NS077543 / NS / NINDS NIH HHS / United States
2R01 NS45491 / NS / NINDS NIH HHS / United States
CA-62203 / CA / NCI NIH HHS / United States
NS-45283 / NS / NINDS NIH HHS / United States
NS-52789 / NS / NINDS NIH HHS / United States
NS072793 / NS / NINDS NIH HHS / United States
P30 CA062203 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
P30-ES002109 / ES / NIEHS NIH HHS / United States
PN2EY016525 / EY / NEI NIH HHS / United States
R01 GM089903 / GM / NIGMS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States